Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis.
EBioMedicine. 2019 Mar 21. pii: S2352-3964(19)30174-4. doi: 10.1016/j.ebiom.2019.03.034. [Epub ahead of print]
|Authors/Editors:||Heun Y, Pircher J, Czermak T, Bluem P, Hupel G, Bohmer M, Kraemer BF, Pogoda K, Pfeifer A, Woernle M, Ribeiro A, Hübner M, Kreth S, Claus RA, Weis S, Ungelenk L, Krötz F, Pohl U, Mannell H.|
BACKGROUND Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence.
METHODS Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation. SHP-2 activity was assessed by dephosphorylation of pNPP, ROS production was measured by DCF oxidation and protein interactions were assessed by proximity ligation assay. Vascular inflammation was studied in the mouse cremaster model and in an in vitro flow assay.
FINDINGS We identified ROS-dependent inactivation of the tyrosine phosphatase SHP-2 to be decisive for endothelial activation in sepsis. Using in vivo and in vitro sepsis models, we observed a significant reduction of endothelial SHP-2 activity, accompanied by enhanced adhesion molecule expression. The impaired SHP-2 activity was restored by ROS inhibitors and an IL-1 receptor antagonist. SHP-2 activity inversely correlated with the adhesive phenotype of endothelial cells exposed to IL-1β as well as sepsis serum via p38 MAPK and NF-κB. In vivo, SHP-2 inhibition accelerated IL-1β-induced leukocyte adhesion, extravasation and vascular permeability. Mechanistically, SHP-2 directly interacts with the IL-1R1 adaptor protein MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3-K to MyD88.
INTERPRETATION Our data show that SHP-2 inactivation by ROS in sepsis releases a protective break, resulting in endothelial activation.